Use of a vitamin combination for the treatment of primary headaches

ABSTRACT

Use of a combination of two vitamin compounds, i.e. riboflavin (also known as vitamin B 2 ) and nicotinic acid (also referred to as niacin) or, as an alternative thereto, the corresponding amide, i.e. niacinamide or nicotinamide (also known as vitamin PP) for the treatment of various forms of primary headache, such as classical migraine or migraine with an aura, common migraine or migraine without an aura, complicated migraine and cluster headache or histamine headache. The invention also concerns compositions for the treatment of primary headaches which are based on the two aforesaid active ingredients.

The present invention concerns the use of a vitamin combination for thetreatment of primary headaches. More particularly, this inventionrelates to the use of a combination of two vitamin compounds, i.e.riboflavin (also known as vitamin B₂) and nicotinic acid (also referredto as niacin) or, as an alternative thereto, the corresponding amide,.i.e. niacinamide or nicotinamide (also known as vitamin PP) for thetreatment of various forms of primary, headaches, among which commonmigraine, classical migraine or migraine with aura, duster headache andcomplicated migraine.

BACKGROUND OF THE INVENTION

As it is known, the term headache is currently taken to mean any form ofmore or less intense pain localised in the head. This pain may havevarious origins and in only about 10% of the cases it is caused by aspecific organic illness, Under this profile it is possible todistinguish primitive or primary headaches, the cause of which is notaccurately identifiable, and secondary headaches, which alwaysconstitute the symptom of another primary disorder, Examples ofsecondary headaches include sinusitis, headache due to cerebralhemorrhage, headache due to endocranial hypertension (in particular,caused by brain tumors), headache caused by infective meningitis andheadache due to arterial hypertension. In all cases, the diagnosis callsfor an accurate examination that not only takes the pain characteristicsinto account, but also the familiarity and relations with otherdisorders, causal factors and reactions to various pharmaceuticals, andin most cases requires a series of tests such as a blood test, X-rays ofthe cranium and cervical column, EEG and echography,

Once having excluded that the symptoms are linked to a different basicdisorder, then it is likely that the disorder is one of the possiblearms of primary headaches, often referred to as a “migraine”, whichaffect about 20-30% of the population (prevalently women). According toone of the current classifications, this may be of one of the followingfour forms: 1) classical migraine, i.e. with an aura; 2) commonmigraine, i.e. without an aura; 3) complicated migraine; 4) clusterheadache.

Apart from the cluster headache, the aforesaid other forms of migrainegenerally consist of a pulsating periodic headache affecting one half ofthe cranium, and often associated with nausea and/or vomiting. Thedisorder generally starts in childhood, during adolescence and earlyadulthood and decreases in intensity and frequency over the years. Inparticular, a classical migraine starts with the so-called aura,consisting of protracted neurological symptoms for 30 minutes andincludes photophobia, flashing scotoma (ie. bright flashing sensationsbefore the eyes, with jagged edging similar to a wall), vertigo andtinnitus. With common migraines the headache arise with-out a prioraura, but often involves nausea or vomiting. Complicated migraines areinstead characterised by headaches associated with particularneurological symptoms that may precede or accompany them. In particular,there may be paresthesia and hypoesthesia of the lips, face, hand andleg of al hemi-soma, sometimes associated with aphasic disorders, or oneend of an arm or leg may become hyposthenic or plegic simulating anictus. The sensitive disorders or feelings of weakness extend slowlyfrom one side of the body to the other for a period a few minutes.Usually, after an attack, there in a complete return to normality, butthere may also be permanent deficiencies among which hemianopsia,hemiplegia and hemianestesia. Cluster headache, also referred to asparoxysmal nocturnal headache, hemicranial neuralgia, histamine headacheand Horton's syndrome, is four times more common in men than in women,and is characterised by a constant unilateral orbital pain generallybeginning two or three hours after sleep onset. The pain is intense andsteady but not pulsating, and involves lachrymation, nasal congestion,rhinorrhea and then myosis, reddening and oadema of the cheek that lastsfor about 30 an hour. This form of headache tends to occur cyclicallyduring the right for several weeks or months (hence the name “cluster”)and is then followed by a complete recovery for months or even years.Episodes of cluster headache of 2-3 week duration may arise severaltimes in a lifetime.

The physiopathological mechanisms of the various forms of primaryheadache have been the subject of many studies and to date nopathogenetic theory that appears satisfactory to all researchers hasbeen proposed. Many factors have been put forward as possible causes ofa migraine attack, among which stress, physical strain, the weather,hormone fluctuations, bright lights and the intake of certain foods orbeverages, such as those containing caffeine or alcohol. In any case,the migraine symptoms are always associated with variations in cerebralblood flow, presumably as a result of changes in blood vesseldimensions: normally, the prodromes are accompanied by arterialconstriction and a reduction in cerebral blood flow, and are followed byblood vessel dilation corresponding to the actual headache onset.However, the factors which determine these changes in cerebral bloodflow and the mechanisms through which such changes are linked to painare controversial. One of the hypotheses claims that a migraine is dueto a neurovascular disorder of the central nervous system (inparticular, of the hypothalamus and brainstem) which involvesalterations in vasomotor regulation, while another hypothesis interpretsthe disorder as a systemic metabolic imbalance with attacks caused byintravascular factors associated with serotonin (or 5-hydroxytriptamine,5-HT) variations in the metabolism. It has been found, though, thatmigraines are accompanied by variations in platelet serotonin levelswith a fall in these levels, during a migraine attack, due to therelease —associated with increased urinary excretion —of its mainmetabolite, 5-hydroxyindolacetic acid.

According to some more recent observations, during a migraine attackthere is an overflow of plasmatic proteins and the development oflocalised inflammation of intracranial blood vessels, together with theactivation of trigeminal innervation of cerebral blood circulation. Thisphenomenon also sees the action of certain peptidic neurotransmitterswhich have a vasodilatory effect and are contained in the nerve fibresof the trigeminovascular system, in particular the CGRP (calcitoningene-related peptide) and SP (substance P). These neurotransmittersappear to be particularly important in pain transmission and they arethought to be also involved in local tissue reactions of an inflammatorytype. In particular, it has been demonstrated that substance P causesprotein overflow and the typical inflammatory reaction triggered by thedegranulation of mastocytes even in the brain dura mater, the connectivetissue covering and protecting the brain matter, and which contains thecerebral blood vessels and their accompanying nerve fibres (Moskowitz M.A., Basic mechanisms in vascular headache, Neual. Clin. 8:801-415, 1990;Moskowitz M. A. and Outrer F. M., Sumatripan, a receptor-taretedtreatment of migraine, Ann. Revs Med., 44:145-154, 1993; May A., GoadsbyP. J., The Trigeminovascular System in Humans: PathophysiologicalImplications for Primary Headache Syndromes of the Neural Influences onthe Cerebral Circulation, J. Cereb. Blood Flow Metab., 19:115-117,1999).

As well as the two aforesaid vasodilating neurotransmitters andserotonin, other chemical agents seem to be involved, depending on thecases, in causing headache pain, such as histamine (as the termhistamine headaches attributed to the cluster headache implies),thromboxan A₂, prostaglandins and quinines. Current migraine treatmentpartly takes these chemical agents into account with therapies that aimto neutralise their action. This is the case, for example, withanti-inflammatory drugs and analgesics currently used in particularcases of headache. Other currently used treatments are ergotamine andits derivatives; ergot alkaloids that appear to be mostly active againstclassical and common migraines, and only if taken early during anattack; metisergide, an antiserotoninegic drug (a strong antagonist of5-HT₁ recptors), especially useful as a preventive measure; and theselective agonists of the 5-HT₁ receptors, above all, sumatryptan. Thelatter can trigger 5-HT₁ serotonin receptors which mediate localisedvasoconstriction at the carotid level, thereby reducing blood flow tothe extra and intracranial tissues. Although effective in reducing theheadache pain symptom, these products are not devoid of side-effectsMoreover, to develop a quick response they need to be administered bysubcutaneous injection.

SUMMARY OF THE INVENTION

An object of the present invention is therefore to provide aconsistently effective pharmacological therapy, that is easy toadminister and devoid of harmful side-effects, suitable for thesuccessful resolution of various forms of primary headache that havehitherto been unsatisfactorily treated or unresolved. To achieve suchpurpose, in the frame of the research leading to the present invention aparticular vitamin combination has been taken into consideration,composed of nicotinic or 3-pyridincarboxylic acid, also known as niacin(or, in alternative thereto, nicotinamide, also referred to as vitaminPP) and riboflavin (also known as vitamin B₂).

The first ingredient of the aforesaid combination, nicotinic acid, is awell-known vitamin factor commonly found in a great many vegetable andanimal tissues, and particularly in food sources such as meat, poultry,fish, liver, kidney, eggs, nuts, butter, milk and yeast. In humanbeings, nicotinic acid may also be synthesised from the amino acidtryptophan, but the latter source is normally insufficient to meet thedietary requirements for this vitamin. In fact, the alternative name ofvitamin PP (or P.P. factor, i.e. pellagra preventive factor) that iscommonly used is due to its critical activity in the prevention ofpellagra. The latter is a disease caused by vitamin deficiency, thatoccurs in dietary regimens poor in tryptophan (or, correspondingly,niacin or nicotinamide), such as a diet mainly based on maize and withvery little animal protein intake.

Nicotinic acid functions in the body only after it has been convertedinto one or the other of the physiologically active forms —nicotinamideadenine dinucleotide (NAD) or nicotinamide adenine dinucleotidephosphate (NADP). These serve as coenzymes for a wide variety ofproteins that catalyse oxidation-reduction reactions essential fortissue respiration. This biological process is the result of severaloxidation-reduction reactions occurring within the cells, in particularin the mitochondria, in order to oxidise that part of material reachingthe cells (through the bloodstream) so as to be used for energyproduction. Among the various enzymes responsible for oxidativeprocesses (oxidoreductases), that perform their function by accepting aH₂ molecule from the substrate, the enzymes known as dehydrogenasescannot use molecular oxygen as an immediate acceptor of the hydrogentaken from the substrate, but have to use the pyridine coenzymes (NADand NADP) as acceptors. Hence, the presence of these coenzymes isvitally important for the proper development of the biochemical cyclesthat produce energy, such as from sugars (glycolysis and Krebs cycle)and from fatty acids (beta-oxidation), or in the metabolic pathwayleading to urea (ornithine cycle).

In view of the above, the presence of adequate levels of nicotinic acidand/or nicotinamide (or tryptophan) in the body is an essentialrequirement for the regular functioning of the gastrointestinal tract,for a healthy skin, for nervous system maintenance and for the synthesisof the sex hormones. Symptoms of deficiency may be muscular weakness,generalised asthenia, loss of appetite, cutaneous eruptions, stomatites,insomnia, nausea and migraine. As recalled above, severe deficiencieslead to pellagra. The doses of nicotinic acid, nicotinamide or ofsuitable derivatives (such as methyl nicotinate) normally used fortreating pellagra are of about 50 mg, by the oral route, up to 10 timesa day. If oral administration is not possible, then intravenousinjections of 25 mg of the vitamin may be administered twice a day.

It is also well-known that nicotinic acid and nicotinamide are effectivein improving blood circulation and in lowering cholesterol levels. Asregards the first effect, some products for the topical administrationcontaining nicotinic acid are available, having the function of atopical rubefacient and analgesic, for the relief of muscular pain andrheumatism. In these products, niacin assumedly enhances the peripheralblood circulation since it dilates subcutaneous blood vessels afterpenetrating the skin.

As regards the second effect mentioned above, niacin is used in systemicadministration, i.e. by the oral or parenteral route, at higher dosesthan those mentioned above for the prophylaxis and treatment of pellagra(i.e. 2-6 g per day) in preparations for hyperlipidemia therapy, forlowering cholesterol levels in the blood. However, at the high systemicdoses required by this treatment, both nicotininc acid and nicotinamidehave shown a certain number of adverse side-effects, includinggastrointestinal reactions (abdominal pain and nausea), hepatotoxicityand, above all, flushing (cutaneous erythema) often accompanied bywarmth, tingling and itching.

In order to reduce these side-effects while maintaining the dosesrequired for antilipemic treatment, changes have been proposed for thenicotinic acid molecule by creating various derivatives as well ascombinations of niacin or nicotinarnide with other active ingredients oradjuvants, and particular formulations and dosages. Examples of thesevariants are described in the European patent application EP-A-0349235(and the corresponding U.S. Pat. No. 4,965,252), concerning anantihyperlipidemic composition based on nicotinic acid for oraladministration where the undesired side-effects of the active ingredientare eliminated by mixing with guar gum, and in the international patentpublication WO-A-9632942, concerning a combination of a therapeuticallyeffective amount of methyl nicotinate and a non-steroidalanti-inflammatory drug (NSAID), preferably in a sustained release form,in the aim of reducing the irritating action characterising niacin whenused as an antihyperlipemic agent.

Within the studies leading to the present invention, in the first phaseit was checked that, while the systemic administration of nicotinic acidor nicotinamide in doses well below those employed for the treatment ofhypercholesterolemy—i.e. the typical dosage used when using the sameagents for the prevention and treatment of pellagra—does not lead to thesecondary reactions that have been reported for high doses, neverthelessit is not very effective in combating the forms of headache consideredby this invention. Actually, according to the clinical experimentationcarried out and reported in part further on, neither the commonmigraine, classical migraine and the so-called complicated migraine, northe cluster headache have appeared to satisfactorily respond to drugsbased on only nicotinamide or on only nicotinic acid. On the other hand,the desired effect is obtained when niacin or nicotinamide areadministered systemically in a combination with another known vitaminagent, i.e. riboflavin or vitamin B₂.

This second active ingredient, having chemical name7,8-dimethyl-10(D-ribo-2,3,4,5-tetrahydroxypenthyl)isoalloxazine, isitself also a nutritional factor of primary importance that is mainlyfound in milk, eggs, cheese, liver, heart, kidney and green vegetables.Riboflavin performs its own biological functions in the body in the formof an essential component of two coenzymes, riboflavin phosphate,commonly known as flavin mononucleotide (FMN) and flavin adenindinucleotide (FAD).The latter two coenzymes, like the two aforesaidpyridine enzymes (i.e. NAD and NADP), cooperate with respiratoryflavo-proteins in oxidising the substrate by accepting a hydrogenmolecule from it s but, unlike NAD and NAOP, may release the hydrogenmolecule directly to the molecular oxygen. Moreover, theoxidation-reduction potential of FMN and FAD is such that these twocompounds are able to oxidise the reduced pyridine coenzymes. In factthe function of flavoproteins (of which, as already mentioned, FMN andFAD constitute the coenzymes) is, on the one hand, to directly oxidisethe substrates and, on the other, to contribute to pyridine cenzymefunctioning by re-oxidising them once the latter have been reduced afterinteracting with a substrate.

DETAILED DESCRIPTION OF THE INVENTION

In view of the above and considering that in practice the pyridineco-enzymes (NAD and NAL)P) can perform their function only in thepresence of flavo-proteins, i.e. of riboflavin, it may be seen how thepresence of both these agents is necessary for the correct functioningof the biochemical mechanisms governing cell metabolism, Without wishingto be bound by any particular theory concerning the mechanism of actionof the proposed combination of active ingredients, it is considered thatboth niacin and riboflavin play a crucial role in the metabolism ofmastocytes. A deficiency of either of these agents would adverselyaffect the energy production phase of the metabolic chain that leads tothe activation of these calls, that is mainly responsible for releasingthe biochemical mediators and neurotransmitters mentioned above. As isknown, mastocytes or mast cells are found in organs rich in connectivetissue, such as the shin and the respiratory and gastrointestinal tractsand—as regards those aspects concerning the present invention—thecerebral dura mater, and are characterised by the presence of granuleswhich may be secreted by the mast cell following its activation, in thisway releasing the various mediators and neurotransmitters mentionedabove.

According to the present invention, it has been considered that once themastocytes are activated then a series of enzymatic reactions take placein the cell that include an energy-requiring phase and terminate wit thede-granulation of the mastocyte and the release of preformed or newlysynthesised mediators. In view of the results of the clinical trialspresented below It is reasonable to hypothesise that migraine or clusterheadache pain is caused by an energy-controlled alteration in themetabolic mechanism leading to the mastocytic secretion of the mentionedbiochemical mediators and neurotransmitters, and that the systemicadministration of a suitable dose of niacin or nicotinamide togetherwith riboflavin will provide the body with the necessary NAD/NADP andFAD/FMN in order to appropriately modulate the activity of these cells

With specific reference to migraines, and particularly to instanceslinked to premenstrual syndrome such as pain, depression, migraine andfatigue, the international patent publication WO-A-9917612 suggestsusing a formulation based on serotonin, probably starting from thealready reported idea of the drop in serotonin levels during a migraine.According to this document. the proposal of administering serotonin fortreating various problems including headaches had already been putforward, but oral administration was considered impossible due to theoxidising degradation of this active ingredient in the gastrointestinaltract. This meant that it was necessary to use a precursor of serotonininstead of serotonin itself—L-tryptophan—for It to be converted intoserotonin after administration. According to the publication at issue,on the contrary, the oral administration of an effective quantity ofserotonin was suggested In combination with a suitable antioxidant (e.g.vitamin C or vitamin E), In order to prevent serotonin degradation inthe gastrointestinal tract. The publication also suggested formulationsin which the two mentioned agents are combined with adjuvants selectedfrom within the broad group of vitamin factors and, among these, alsoriboflavin and niacin or nicotinarnde. It is worth noting that thespecification exclusively attributes to serotonin dosed in a sufficientquantity to take the haematic level of this neurotransmitter abovenormal levels—a therapeutic action for the treatment of premenstrualsyndrome. The experimental data presented show that the subjectivesymptoms of this disorder are depression, migraines and generic“premenstrual symptoms”. In view of all the above, it is obvious thatthe formulation described in the publication concerned is notexploitable for a valid effective treatment of the primary headacheforms considered here.

Accordingly, the present invention specifically provides the use of acombination of nicotinic acid or of nicotinamide with riboflavin for theproduction of a medicament for the treatment and/or the prophylaxis ofprimary headache forms. More specifically, this preparation is effectivefor the treatment and/or prophylaxis of common migraines, classicalmigraines, complicated migraines and cluster headaches.

For the therapeutic indications of the present invention, the two activeingredients must be administered systemically—particularly via the oralor parenteral route—using a dosage of between 0.5 and 750 mg per day ofniacin or of nicotinamide, and between 0.1 and 250 mg per day ofriboflavin. Preferably, this combination will include niacin ornicotinamide and riboflavin in a ratio between 40:1 and 10:1 (nicotinicacid or nicotinamide: riboflavin), while the best ratio is 20:1(niacinamide: riboflavin). According to a particularly effectivetherapeutic protocol, 50 mg of nicotinamide+2.5 mg of riboflavin areadministered orally twice a day, continuing the treatment until themigraine disappears. Then, in some particular cases, the treatment iscontinued for another short period and, if necessary, continuing withhalf doses of the vitamin combination for about another 15 days.

The compounds of the invention may be administered in different ways,for example via the oral or parenteral route. In such administrations,the two active ingredients may be incorporated in traditionalpharmaceutical formulations in the form of solid or liquid dosages.These may contain the usual additives employed in pharmaceuticaltechniques such as, for example, sweeteners, flavourings, colourings,coverings and preservatives, inert diluents such as calcium carbonate,sodium carbonate, lactose and talc, binding agents such as amide,gelatine and polyvinylpyrrolidone, suspending agents such as methylcellulose or hydroxyethyl cellulose and inhibitors such as lecithin,polyoxyethylene stearate and polyoxyethylene sorbitan monooleate,reducing agents such as ascorbic acid and its salts. The formulationsfor parenteral administration (more specifically, to be injectedintravenously or intra muscularly) may also contain the activeingredients dissolved or suspended in distilled water, together with themost common pharmaceutically acceptable excipients.

A particularly effective therapeutic protocol for the treatment ofvarious forms of headache is the following. 1^(st) phase: 50 mg ofnicotinamide+2.5 mg of riboflavin twice a day until the headachedisappears; then continue with 50 mg of nicotinamide+2.5 mg ofriboflavin per day for 15 days; 2^(nd) phase (optional): 50 mg ofnicotinamide+2.5 mg of riboflavin per day for 15 days a month for theprophylaxis. It is advisable to take the compounds via the oral route,after the main meals, with abundant water (at least half a glass). Incases where pain returns after suspending the treatment, it will benecessary to start from the 1^(st) phase again.

As already noted, alternatively to oral administration it is alsopossible to use injections, with a preferred dosage of 20 mg ofnicotinamide+1 mg of riboflavin once or twice a day.

According to a further specific aspect, the present invention alsoconcerns a composition for the treatment and/or prophylaxis of primaryheadaches using as active ingredients a combination of nicotinic acid ornicotinamide and riboflavin. The particularly preferred characteristicsof these compositions are provided in the attached claims. It isobvious, however, that the two active ingredients of the invention mustnot necessarily be contained in the same product, since it is alsopossible to administer them separately as long as the dosage andtherapeutic protocol are the ones illustrated above.

Some experimental results obtained according to the present invention,including clinical data on the performance of the proposed combinationin comparison with the use of nicotinic acid or nicotinamide alone, arereported below for merely illustrative purposes.

1^(st) Series of Tests—Treatment with the Nicotinamide-RiboflavinCombination

1^(st) case—a 49-year-old woman with a classical migraine (or a migrainewith an aura). The patient had been suffering from classical migrainesymptoms for 30 years. Initially, the symptoms were located in the righttemporal region and later spread to the top and to the left temple withcharacteristic pulsations, accompanied by photophobia, vertigo andbuzzing ears. The attacks lasted for about 10 days on a monthly basis.She had been undergoing treatment for a certain period at theCephalalgia Unit of Florence University, where her therapy was based onvasoconstrictors (ergotamines) and anti-inflammatory analgesics, whichwere not successful.

Later, during a migraine attack, the patient started a treatment basedon 50 mg of nicotinamide+2.5 mg of riboflavin taken orally twice a day.Just two days into the treatment the symptoms were greatly reduced andthey completely disappeared on the third day. During this period thepatient had completely suspended the old therapy. She continued with thenew treatment, according to the present invention, for another 7 days tothen temporarily suspend it. Later on, the dosage was halved for 10 daysa month for preventive purposes. In the next 4 months from starting thetreatment, the patient no longer had any migraine attacks.

2^(nd) case—a 25-year-old woman with a common migraine (or a migrainewithout an aura). The patient suffered from a common migraine startingon the right side with the pulsating characteristic and accompanied bynausea.

The problem had been diagnosed about 9 years before at a neurologydepartment of Rome's “La Sapienza” University. Since then she had takenanalgesics and vasoconstrictors for about 8 consecutive days every twoweeks, but benefited little from them.

Later, on medical advice, at the onset of a migraine attack the patientstarted taking 50 mg of nicotinamide+2.5 mg of riboflavin orally twice aday. After two days the pain dropped and then disappeared. She continuedtreatment for another 10 days with this protocol and then the dosage washalved.

In the next 6 months from the start of the treatment she had no furthermigraine attacks.

3^(rd) case —a 36-year-old woman with complicated migraine. The patienthad been suffering from complicated migraines since the age of 23 years.

She had undergone treatment at the Cephalalgia Unit of Rome's “LaSapienza” University with analgesics, anti-inflammatory ergotamines and,finally, also anti-serotoninergic drugs. These treatments not only ledto very slight improvements, but even brought on considerable adverseside-effects such as myalgia, neck and limb pains, and asthenia. Beforestarting the treatment of the present invention, the patient had aright-side hemicranial pain with photophobia, buzzing ears and lefthemisoma motility disorders.

She was prescribed a therapy based on 50 mg of nicotinamide+2.5 mg ofriboflavin taken orally twice a day. After 3 days the symptoms weregreatly reduced and then disappeared completely on the fifth day. Thepatient continued to follow the same treatment for another 15 days andthen went on a 15-day treatment every month with half the dosage. After7 months from the start of treatment the check-ups every 15 days showedthe absence of any migraine attacks.

4^(th) case—a 32-year-old man with cluster headaches. The patient hadbeen suffering from nocturnal headaches for about 15 years. Theheadaches started about 3 hours after sleep onset and presented a leftorbital pain, lachrymation, nasal congestion and an oedema of the leftcheek. He had been treated from the start of the symptoms at theCephalalgia Unit of Rome's “La Sapienza” University, where a clusterheadache (or histamine headache or Horton's syndrome) was diagnosed. Thetreatment consisted of ergotamines and antidepressants which only gavevery slight relief.

The patient was thus treated with 50 mg of nicotinamide+2.5 mg ofriboflavin taken orally twice a day After 3 days the nocturnal headachesymptoms completely disappeared. He continued with the therapy foranother 15 days and then the dosage was halved and treatment continuedfor 15 days a month. In the next 19 months of observation he had nofurther cluster headache episodes.

2^(nd) Series of Tests—Treatment in Two Phases: First with onlyNicotinamide and then with the Nicotinamide-Riboflavin Combination

1^(st) case—a 35-year-old woman with a classical migraine (or migrainewith an aura). The patient had been suffering from classical migrainesymptoms for 15 years and had photophobia, flashing scotoma and vertigo.The problem had been diagnosed at the at the Cephalalgia Unit of Rome's“La Sapienza” University, where she was prescribed a treatment based onergotamines, analgesic and anti-inflammatory drugs which were not verysuccessful. The symptoms were located on the right side, occurred abouttwice a month and lasted a week, on average. When suffering frommigraines the patient could not perform any activity. The acute episodeswere preceded by photophobia, buzzing ears and visual disorders(scotoma).

During a migraine attack the patient had started taking 50 mg ofnicotinamide orally twice a day and the migraine symptoms attenuatedafter 5 days but did not disappear completely. She continued with thetreatment and after about 10 days the migraine returned, even if of alesser intensity. The patient was then treated with 50 mg ofnicotinamide+2.5 mg of riboflavin taken orally twice a day and themigraine disappeared after 3 days. She continued with the vitamincombination for another 15 days and then switched to taking the vitamincombination just once a day for 15 days a month. After 6 months fromstarting the treatment, the patient no longer had any migraine attacks.

2^(nd) case—a 32-year-old man with complicated migraine. The patient hadbeen suffering from complicated migraines since the age of 25 years. Thesymptoms were a pulsating type migraine localised on the right andpreceded by photophobia and flashing scotoma. During migraine attacks heat times also had hyposthenia and a reduced sensibility of the left armand leg. These symptoms arose about twice a month. He had initiallyundergone treatment at the Cephalalgia Unit of Rome's Gemelli Hospitalwith anti-inflammatory and ergotamine drugs and later alsoanti-serotoninergic drugs. These treatments only led to very slightimprovements.

Thus, during a migraine attack, the patient started treatment based on50 mg of nicotinamide taken orally twice a day and the problem wasattenuated after 6 days. After adding 2.5 mg of riboflavin, taken orallytwice a day, to the above therapy every symptom disappeared afteranother 2 days. The patient continued to take the two-vitamincombination at half dosage for 15 days a month. A check-up one yearafter starting the treatment revealed that he no longer had any migraineattacks.

3^(rd) case—a 32-year-old woman with a common migraine. The patient hadbeen suffering from the disorder for 15 years and the migraine occurredon the left side, accompanied by nausea. The painful episodes occurredevery 15 days, on average. After being told she had a common migraine,she started treatment at the Cephalalgia Unit of Florence University.She was treated with anti-inflammatory, analgesic and ergotamine drugsand later also with anti-serotoninergic drugs, but had little relieffrom them.

The patient was then treated with 50 mg of nicotinamide taken orallytwice a day and the migraine was partially attenuated in about 5 days.In a later check-up she was prescribed 2.5 mg of riboflavin taken orallytwice a day in addition to the nicotinamide, and the migrainedisappeared in another 2 days. The patient continued the same treatmentfor another 15 days and then the dosage was halved for 15 days a month.In the next 16 months from the start of the treatment she had no furthermigraine attacks.

4^(th) case—a 42-year-old man with cluster headaches. The patientsuffered from cluster headaches that made him wake up in the night withlacerating head pains. The pains were accompanied by lachrymation andrhinorrhea. The diagnosis had been made 20 years earlier at theCephalalgia Unit of Rome's “La Sapienza” University and he had receivedtreatment with ergotamines and antidepressants which only gave veryslight relief.

The patient thus started treatment with 50 mg of nicotinamide takenorally twice a day and the headaches attenuated after 5-6 days. Later,2.5 mg of riboflavin were also added to the treatment with nicotinamideand the headaches completely disappeared after 2 days. He continued totake 50 mg of nicotinamide and 2.5 mg of riboflavin orally per day for15 days a month In the next 20 months of follow-up he had no furthercluster headache episodes.

The foregoing experimental report clearly shows the superioreffectiveness of the vitamin combination proposed in the presentinvention for the treatment of various forms of primary headaches, bothin comparison with similar treatments suggested by the prior art andwith those based on nicotinamide or niacin only.

The present invention has been disclosed with particular reference tosome specific embodiments thereof, but it should be understood thatmodifications and changes may be made by the persons skilled in the artwithout departing from the scope of the invention as defined in theappended claims.

1. A method for the treatment of a migraine or cluster headache in asubject in need of the same, said method consisting of administering tosaid subject a pharmaceutically acceptable vehicle or carrier, 0.5 to750 mg of nicotinic acid or of nicotinamide, and 0.1 to 250 mg ofriboflavin per day, in a ratio by weight of from 40:1 to 10:1(nicotinicacid or nicotinamide: riboflavin).
 2. The method according to claim 1,wherein said migraine headache is a migraine headache selected from thegroup consisting of common migraine, classic migraine, and complicatedmigraine.
 3. The method according to claim 1, wherein said ratio byweight is 20:1.
 4. The method according to claim 1, wherein thecomposition consists of 50 mg of nicotinic acid or nicotinamide and 2.5mg of riboflavin.
 5. The method according to claim 1, further comprisingtreating the headache until the headache disappears.
 6. The methodaccording to claim 5, further comprising treating the subject foranother 15days with half dosages of the nicotinic acid or nicotinamideand riboflavin.